Dysregulation of angiopoietin-1 plays a mechanistic role in the pathogenesis of cerebral malaria.
Dysregulation of angiopoietin-1 plays a mechanistic role in the pathogenesis of cerebral malaria.
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DOI：
10.1126/scitranslmed.aaf6812
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发表时间：
2016-09-28
影响因子：
17.1
通讯作者：
Kain KC
中科院分区：
文献类型：
--
作者：
Higgins SJ;Purcell LA;Silver KL;Tran V;Crowley V;Hawkes M;Conroy AL;Opoka RO;Hay JG;Quaggin SE;Thurston G;Liles WC;Kain KC
脑型疟疾是全球发病率和死亡率的主要原因。与单独使用抗疟药物治疗相比，针对脑型疟疾潜在病理生理的干预措施可能改善结果。微血管渗漏在脑型疟疾发病中起重要作用。血管生成素(Ang) -Tie-2系统是血管功能的关键调节器。我们在乌干达严重疟疾儿童和实验性脑疟疾临床前小鼠模型的前瞻性研究中表明，Ang-1表达和可溶性Tie-2表达与疾病严重程度和结果相关。在脑型疟疾小鼠模型中，Ang-1是维持血管完整性和存活所必需的。治疗性给予Ang-1可保持血脑屏障的完整性，并与青蒿琥酯治疗相结合，比单独使用青蒿琥酯治疗可提高生存率。这些数据确定了Ang-Tie-2轴失调在脑型疟疾发病机制中的作用，并支持评估基于Ang-Tie-2的干预措施作为治疗严重疟疾的潜在辅助疗法。
Cerebral malaria is a leading cause of global morbidity and mortality. Interventions targeting the underlying pathophysiology of cerebral malaria may improve outcomes compared to treatment with antimalarials alone. Microvascular leak plays an important role in the pathogenesis of cerebral malaria. The angiopoietin (Ang)–Tie-2 system is a critical regulator of vascular function. We show that Ang-1 expression and soluble Tie-2 expression were associated with disease severity and outcome in a prospective study of Ugandan children with severe malaria and in a preclinical murine model of experimental cerebral malaria. Ang-1 was necessary for maintenance of vascular integrity and survival in a mouse model of cerebral malaria. Therapeutic administration of Ang-1 preserved blood-brain barrier integrity and, in combination with artesunate treatment, improved survival beyond that with artesunate alone. These data define a role for dysregulation of the Ang–Tie-2 axis in the pathogenesis of cerebral malaria and support the evaluation of Ang–Tie-2–based interventions as potential adjunctive therapies for treating severe malaria.
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DOI：
10.1038/nsb880
发表时间：
2003-01-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
Davis, S;Papadopoulos, N;Yancopoulos, GD
通讯作者：
Yancopoulos, GD
影响因子：
48
作者：
Birbeck, Gretchen L.;Molyneux, Malcolm E.;Taylor, Terrie E.
通讯作者：
Taylor, Terrie E.
影响因子：
168.9
作者：
Dondorp, Arjen M.;Fanello, Caterina I.;White, Nicholas J.
通讯作者：
White, Nicholas J.
影响因子：
11.2
作者：
Daly, Christopher;Eichten, Alexandra;Thurston, Gavin
通讯作者：
Thurston, Gavin
影响因子：
8.8
作者：
Huang, Yao Qi;Sauthoff, Harald;Hay, John G.
通讯作者：
Hay, John G.